The present invention relates to a new process for preparing pharmaceutically active compounds and intermediates therefor.
Pharmaceutical products with antidepressant and anti-Parkinson properties are described in U.S. Pat. No. 3,912,743 and U.S. Pat. No. 4,007,196. An especially important compound among those disclosed is paroxetine, the (xe2x88x92) trans isomer of 4-(4xe2x80x2-fluorophenyl)-3-(3xe2x80x2,4xe2x80x2-methylenedioxy-phenoxymethyl)-piperidine. This compound is used in therapy as the hydrochloride salt to treat inter alia depression, obsessive compulsive disorder (OCD) and panic.
This invention aims to overcome disadvantages in the existing processes for preparation of such compounds and so to provide alternative processes for their manufacture.
This invention has been developed on the basis that compounds of structure (1) below are either valuable chemical intermediates useful for the manufacture of important medicinal products, for example paroxetine hydrochloride, or are themselves active compounds, such as disclosed in U.S. Pat. No. 3,912,743 and U.S. Pat. No. 4,007,196.
By reference to Example 4 of U.S. Pat. No. 4,007,196, paroxetine may be prepared from a compound of structure (1) below in which R is methyl, and Z is hydrogen, that is 4-(4xe2x80x2-fluorophenyl)-3-hydroxymethyl-1-methylpiperidine, by reaction with 3,4-methylenedioxyphenol followed by demethylation. In the same Example, 4-(4xe2x80x2-fluorophenyl)-3-hydroxymethyl-1-methyl piperidine is prepared by reduction of 4-(4xe2x80x2-fluorophenyl)-3-hydroxymethyl-1-methyl -1,2,3,6-tetra-hydropyridine (II), which is in turn prepared from 4-(4xe2x80x2-fluorophenyl)-1-methyl-1,2,3,6-tetrahydropyridine (III), by reaction with formaldehyde.
Alternative processes for the preparation of 4-(4xe2x80x2-fluorophenyl)-3-hydroxymethyl-1-methylpiperidine are given in EP-A-022334, by reduction of compounds of structure (A): 
in which Z is alkyl and R is H, alkyl or aralkyl.
The above described processes produce compounds of structure (1) as a mixture of enantiomers. Therefore conversion of compounds of structure (1) to useful pharmaceuticals, such as paroxetine i.e. the (xe2x88x92) trans isomer of 4-(4xe2x80x2-fluorophenyl)-3-(3xe2x80x2,4xe2x80x2-methylenedioxy-phenoxymethyl)-piperidine, will normally require a resolution stage, as described in EP-A-0223334.
This invention provides a process for the preparation of 4-aryl-piperidines of structure (1): 
in which R is hydrogen or an alkyl, aralkyl, aryl, acyl, alkoxycarbonyl, arylalkoxycarbonyl, aryloxycarbonyl group, and Zxe2x80x2 is a 3,4-methylenedioxyphenyl group,
which comprises reduction of a compound of structure (2a) or (2b): 
in which
Y is oxygen or sulphur, and
R and X are as defined above and Z is hydrogen or an alkyl, aralkyl or aryl group, and where Z is other than a 3,4-methylenedioxyphenyl group thereafter converting Z to 3,4-methylenedioxyphenyl.
This invention also provides a process for the preparation of 4-aryl-piperidines of structure (1): 
in which R is hydrogen or an alkyl, aralkyl, aryl, acyl, alkoxycarbonyl, arylalkoxycarbonyl, aryloxycarbonyl group, and Z is hydrogen or an alkyl, aralkyl or aryl group, most suitably where Z is a hydrogen atom or a 3,4-methylenedioxyphenyl group,
which comprises reduction of a compound of structure (2a) or (2b): 
in which
Y is oxygen or sulphur, and
R, X, and Z are as defined above.
When Z incorporates an aryl group, the aryl group, for example phenyl, may be optionally substituted by one or more groups such as halogen or alkyl or alkoxy, or by two substituents linked to form a fused ring. For example, an especially suitable substituent Z is 3,4-methylenedioxyphenyl, as found in paroxetine. Alkyl groups, including, alkyl groups that are part of other moieties such as alkoxy or acyl, are typically C1-6, especially C1-4 groups.
Compounds of structure (2a) and (2b) are believed to be novel and form part of this invention, especially compounds in which X is H, Z is H or 3,4-methylenedioxyphenyl and R is H or C1-4alkyl, especially methyl.
In a first aspect of the process of this invention compounds of structure (2a) or (2b) are reduced to give compounds of structure (1) in which Z is H, that is 3-hydroxymethyl-4-aryl piperidines. Reduction may be accomplished by hydrogenation at atmospheric or above atmospheric pressure using a variety of known catalysts, or using hydride reagents such as lithium aluminium hydride and sodium borohydride, or by a combination of known methods. A particularly useful aspect of this invention is the transformation of 4-aryl-3-carboxyalkyl-1-(optionally substituted)-piperidines to 4-aryl-3-hydroxymethyl-1-(optionally substituted)-piperidines.
It will be appreciated that reduction of esters or carboxylic acids of structure (2) may be carried out stepwise and an intermediate may be isolated, for example a carboxaldehyde, and the reduction of these intermediate compounds to a compound of structure (1) is also included in the scope of this invention.
Intermediate carboxaldehydes are believed to be novel and form part of this invention. A particularly valuable intermediate is 4-(4-fluorophenyl)-5-oxopiperidine-3-carboxaldehyde.
In a second aspect of the process of this invention compounds of structure (2a) and (2b), where Z is not H, are reduced to ethers of structure (1). This may be accomplished by the use of known selective reagents such as diborane and DIBAL, or by Raney nickel desulphurization of a thionoester intermediate. A particularly advantageous ether for the manufacture of paroxetine is the 3,4-methylenedioxyphenyl ether.
Following the reduction to give an ether of structure (1), either or both the groups Z and R may be subsequently converted to a different group Z or R by conventional means, in order to produce the desired pharmaceutical agent. For example, in the preparation of paroxetine, it may be appropriate to convert Zxe2x95x90H to Z=3,4-methylenedioxyphenyl and/or Rxe2x95x90C1-4alkyl to Rxe2x95x90H. This aspect is also included in the scope of this invention.
One advantageous aspect of this profess is that a single enantiomer of the intermediate (2) may be prepared either by enantioselective synthesis or from a chiral precursor, in which case the resolution noted above may be avoided entirely or transferred to an early stage in the overall process.
Starting materials of structure (2a), where Y is oxygen, may be prepared conveniently by carboxyalklyation of a 4-aryl-piperidine-2-one precursor, which may in turn be obtained from the reaction of an activated alkyl 3-aryl-5-hydroxyvalerate with an amine. In a particularly advantageous embodiment of this invention the alkyl 3-aryl-5-hydroxyvalerate is prepared as a single enantiomer by selective reduction of a 3-arylglutarate mono-ester obtained by enzymatic hydrolysis of the pro-chiral dialkyl 3-arylglutarate, for example using pig liver esterase to obtain S-enantiomers and -chymotripsin to obtain R-enantiomers. Suitable dialkyl 3-arylglutarates may be obtained by, for example, reaction of 4-fluorobenzaldehyde with methyl acetoacetate.
The ester group at the 3-position or a group convertible to an ester group may already be present in the starting material or may be introduced for example by reaction of a 2-piperidone of structure (3) firstly with a strong base, such as sodium hydride or lithium hexamethyldisilazide followed by a carboxylating agent, such as a chloroformic ester or thiono chloroformic ester. 
Compounds with structure (2b) where Y is oxygen may be prepared by, for example, reductive cyclisation of 2-cyano-3-(4xe2x80x2-fluorophenyl)-glutarate esters. A similar preparation has been described for the preparation of 3-ethoxycarbonyl-4-(3xe2x80x2-methoxyphenyl)-2-piperidone (Journal of Organic Chemistry (1977) volume 42, pages 1485-1495), but this procedure had been found to be unsuitable for the preparation of compounds with structure (2b) and results in a complex misture of products. A new and efficient process has now been discovered in which 2-cyano-3-(4xe2x80x2-fluorophenyl)glutarate esters, especially diethyl 2-cyano-3-(4xe2x80x2-fluorophenyl)glutarate, are hydrogenated in 1,4-dioxane. Such compounds may be prepared by reaction of, for example, ethyl cyanoacetate and ethyl 4-fluorocinnamate in sodium ethoxide.
Compounds of structure (2a) and (2b) where Y is sulphur can be prepared from the cyclization of analogous thionoesters or by the reaction of piperidones with sulphurizing reagents such as Lawesson""s reagent or phosphorus pentasulphide, as described in Organic Syntheses (1984), volume 62, page 158 and the Journal of Organic Chemistry (1981) volume 46, page 3558. Reduction of the thio-piperidones may be accomplished stepwise, particularly if a reagent such as Raney nickel is used for the first stage. The resulting 4-aryl-3-carboxyalkylpiperidines may then be separately reduced to compounds of structure (1) by conventional reduction, most suitably with hydride reagents such as lithium aluminium hydride.
Suitable starting materials of structure (2) can be prepared by the manner described above or by transesterification of intermediate esters.
It will be appreciated that the reduction of compounds of structure (2) to give compounds of structure (1) may take place stepwise via. inter alia, compounds of structure (2c) and (2d): 
and the reduction of these intermediate compounds, when produced by this process is also included in the scope of this invention.
Compounds of structure (2c) where X is hydrogen, Z is methyl, and R is hydrogen or C1-4alkyl, were described in U.S. Pat. No. 4,007,196, though no procedure was described which is satisfactory for large scale manufacture. These problems have been overcome in the pending application GB9700690.2. The preparation of compounds of structure (2c), where R and Z are alkyl, by reduction of quaternary pyridinium salts have also been described in EP 0219934.
Compounds of structure (2c) other than those described in the above mentioned patent applications and compounds of structure (2d) are novel and form part of this invention. Particularly important compounds of structure (2c) are those where Z is aryl, especially 3,4-methylenedioxyphenyl, which may inter alia be prepared by selective reduction of compounds (2a) or (2b) or by transesterification of other compounds (2c). Compounds of structure (2c) and (2d) may be reduced further to compounds of structure (1).
Alternatively, interrupted or selective reduction of compounds (2a) and (2b) may give rise to novel intermediate alcohols or ethers of structure (4a) or (4b) which may be isolated, and which also form part of this invention: 
In a preferred method for the preparation of compounds of structure (4a) and (4b), compounds of structure (2a) an (2b) are first converted into thioesters which are desulphurised with, for example, Raney nickel. The intermediate thiono esters are also novel and form part of this invention.
Compounds of structure (4a) and (4b) may also be separately prepared by reactions analogous to those described above for the preparation of compounds of structure (2a) and (2b) and employed in the processes of this invention. For example a carbinol of structure (4a) may be prepared by hydroxymethylation of compound (3), and an ether group may be introduced by reaction of (3) with a chloromethyl ether.
Particularly important compounds of structure (4a) and (4b) are those where Z is 3,4-methylenedioxyphenyl, and especially where X and R are both hydrogen. Compounds of structure (4) may be reduced further to compounds of structure (1).
The novel compounds of structure (4) may also be prepared by other methods such as etherification of (4) where Z is hydrogen, or reductive alkylation of aldehydes.
Many of the intermediate compounds in the processes of this invention are novel, and such intermediates form another aspect of this invention.
In a further aspect of the invention, a compound of structure (1) in which Z is a hydrogen atom obtained by processes of this invention may be converted to an active compound disclosed in U.S. Pat. No. 3,912,743 and U.S. Pat. No. 4,007,196 using conventional procedures disclosed therein.
In particular the compound of structure (1) in which in which Z is a hydrogen atom may be used to prepare paroxetine. The paroxetine is preferably obtained as the hydrochloride salt and most preferably as the hemihydrate of that salt, as described in EP-A-0223403. The present invention includes within its scope the compound paroxetine, particularly paroxetine hydrochloride, especially as the hemihydrate, when obtained via any aspect of this invention, and any novel intermediates resulting from the described procedures.
Paroxetine obtained using this invention may be formulated for therapy in the dosage forms described in EP-A-0223403 or WO96/24595, either as solid formulations or as solutions for oral or parenteral use.
Therapeutic uses of paroxetine, especially paroxetine hydrochloride, obtained using this invention include treatment of: alcoholism, anxiety, depression, obsessive compulsive disorder, panic disorder, chronic pain, obesity, senile dementia, migraine, bulimia, anorexia, social phobia, pre-menstrual syndrome (PMS), adolescent depression, trichotillomania, dysthymia, and substance abuse, referred to below as xe2x80x9cthe Disordersxe2x80x9d.
Accordingly, the present invention also provides:
a pharmaceutical composition for treatment or prophylaxis of the Disorders comprising paroxetine or paroxetine hydrochloride obtained using the process of this invention and a pharmaceutically acceptable carrier,
the use of paroxetine or paroxetine hydrochloride obtained using the process of this invention to manufacture a medicament in solid or liquid form for the treatment or prophylaxis of the Disorders; and
a method of treating the disorders which comprises administering an effective or prophylactic amount of paroxetine or paroxetine hydrochloride obtained using the process of this invention to a person suffering from one or more of the Disorders.
This invention is illustrated by the following Examples.